MRE-269

MRE-269 is an IP receptor agonist and an active metabolite of NS 304 (Item No. 10010411).¹ It is formed from NS 304 primarily via carboxylesterase 1 (CES1) in human liver microsomes and via CES2 in human intestinal microsomes.² It binds to the IP receptor (K_i = 20 nM) and increases cAMP levels in human pulmonary artery smooth muscle cells (PASMCs) in a concentration-dependent manner.^1,3 It is selective for the IP receptor over the DP receptor (IC₅₀ = 2.6 µM), EP₁, EP₂, EP₃, and EP₄ receptors (IC₅₀s = >10, 5.8, >10, and 4.9 µM, respectively), FP receptor (IC₅₀ = >10 µM), and TP receptor (IC₅₀ = >10 µM).¹ Due to its selectivity for IP over EP₃ receptors, MRE-269 induces vasodilation equally in both large and small isolated rat pulmonary arteries in a concentration-dependent manner.⁴ It also inhibits ADP-induced platelet aggregation in isolated human and rat platelet-rich plasma (IC₅₀s = 0.21 and 10 µM, respectively).¹ MRE-269 reduces PDGF-induced proliferation of primary PASMCs derived from patients with chronic thromboembolic pulmonary hypertension (CTEPH).⁵

WARNING This product is not for human or veterinary use.

1. Kuwano, K., Hashino, A., Asaki, T., et al. 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304), an orally available and long-acting prostacyclin receptor agonist prodrug. J. Pharmacol. Exp. Ther. 322(3), 1181-1188 (2007).

2. Imai, S., Ichikawa, T., Sugiyama, C., et al. Contribution of human liver and intestinal carboxylesterases to the hydrolysis of selexipag in vitro. J. Pharm. Sci. 108(2), 1027-1034 (2019).

3. Fuchikami, C., Murakami, K., Tajima, K., et al. A comparison of vasodilation mode among selexipag (NS-304; [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide]), its active metabolite MRE-269 and various prostacyclin receptor agonists in rat, porcine and human pulmonary arteries. Eur. J. Pharmacol. 795, 75-83 (2017).

4. Kuwano, K., Hashino, A., Noda, K., et al. A long-acting and highly selective prostacyclin receptor agonist prodrug, 2-{4-[5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304), ameliorates rat pulmonary hypertension with unique relaxant responses of its active form, {4-[5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), on rat pulmonary artery. J. Pharmacol. Exp. Ther. 326(3), 691-699 (2008).

5. Kuramoto, K., Ogawa, A., Kiyama, K., et al. Antiproliferative effect of selexipag active metabolite MRE-269 on pulmonary arterial smooth muscle cells from patients with chronic thromboembolic pulmonary hypertension. Pulm. Circ. 13(2), e12231 (2023).

Matsumoto, N., Singh, N., Lee, K.S., et al. The epoxy fatty acid pathway enhances cAMP in mammalian cells through multiple mechanisms. Prostaglandins Other Lipid Mediat. 162, 106662 (2022).